The compound 1.alpha., 25-dihydroxycholecalciferol is the active component in a variety of pharmaceutical products having use in treatment of diseases related to abnormal serum calcium level. The compound has the generic name calcitriol, and stimulates intestinal absorption of calcium and phosphorous, making it a beneficial constituent of replacement therapy and treatment of hypocalcemia in patients suffering from a diminished ability to produce or metabolize vitamin D.
1.alpha., 25-dihydroxycholecalciferol is reported in the literature to demonstrate an improved effect on conditions in both children and adults. Use of 1.alpha., 25-dihydroxycholecalciferol includes successful treatment of renal osteodystrophy, hypoparathyroidism, osteomalacia, osteoporosis, hepatic osteodystrophy, vitamin D-resistant rickets, vitamin D-dependent rickets, childhood renal failure and neonatal hypocalcemia. The compound is most widely used in patients with chronic renal failure.
The compound 1.alpha., 25-dihydroxycholecalciferol is known to be sensitive to the presence of oxygen in the form of free molecules and other reactive forms. Sensitivity of the drug manifests itself in the form of producing oxidation-based degradants in solution, resulting in the reduction of potency and a change in solution color. The negative effects tend to manifest themselves even after terminal sterilization and during the shelf life of the product.
To decrease overall oxygen sensitivity of the drug solution, most compositions of 1.alpha., 25-dihydroxycholecalciferol generally employ the use of buffers and/or chelating agents to maintain drug stability as measured by potency and color. See, U.S. Pat. Nos. 4,308,264; 4,948,788; and 5,182,274. The buffer systems and/or chelating agents in such products allow the 1.alpha., 25-dihydroxycholecalciferol solutions to be prepared under less stringent conditions for manufacturing and storage.
However, it has been described that the use of buffers and/or chelating agents is related to certain levels of aluminum in the drug solution. Recently, the Food and Drug Administration has recognized that certain levels of aluminum can be undesirable in pharmaceutical compositions. Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition, Federal Register, FDA, HHS Action: proposed rule 21 CFR Part 201, Jan. 5, 1998. As a result, it is desirable to provide compositions having the lowest levels of aluminum that can be attained. To obtain a low aluminum composition of 1.alpha., 25-dihydroxycholecalciferol, buffers and chelating agents have been removed.
Compositions of 1.alpha., 25-dihydroxycholecalciferol which do not employ the use of buffers or chelating agents are not widely known. Literature recognizing any oxygen stable compositions of such nature has not been described. Pending U.S. application Ser. No. 08/900,981 in the name of Li et al. describes 1.alpha., 25-dihydroxycholecalciferol compositions having low levels of aluminum in solution, which can be achieved in part by removing the buffer and chelating components from the solution. Japanese patent 05-238,936 discloses an aqueous formulation of calcitriol comprising a nonionic surfactant and ascorbic acid. Standard methods of removal or preventing the introduction of oxygen are described, but there is no appreciation of the stringent controls on oxygen limits suitable for preparing a stable low aluminum formulation.
We have now determined that the removal of the buffers and chelating agents from the desired low aluminum formulations diminishes the ability of the composition to compensate for the oxygen-sensitivity of the 1.alpha., 25-dihydroxycholecalciferol active agent and other oxygen-sensitive components of the composition. The presence of oxygen in the 1.alpha., 25-dihydroxycholecalciferol in aqueous formulation predominantly comes from exposure to oxygen in the unfilled area of a container carrying the drug solution (headspace) as well as the absorption of gaseous oxygen into the drug solution.
Commercially available methods for controlling oxygen can achieve an oxygen content level of 3-10% in the headspace. These methods for controlling the oxygen content of the headspace are insufficient for reliably controlling the levels of oxygen necessary to obtain a stable low aluminum formulation of 1.alpha., 25-dihydroxycholecalciferol having desirable potency and color over the shelf life of the composition.
Stringent control of the oxygen levels in the headspace provide beneficial effects for decreasing the total oxygen content in the overall composition, including the container headspace and the dissolved oxygen that is absorbed into the drug solution. Consequently, purging a sufficient amount of oxygen from headspace of the composition affords an overall more stable formulation of the oxygen-sensitive drug. We have determined that to provide a stable composition of a 1.alpha., 25-dihydroxycholecalciferol formulation, which is essentially free of buffer or chelating agent, the composition should have less than or equal to about 2.0% oxygen by volume when determined relative to the volume of the headspace in the container.
Therefore, one object of the present invention relates to providing a composition of 1.alpha., 25-dihydroxycholecalciferol having low oxygen levels of less than or equal to 2.0% oxygen in the headspace of a container. These oxygen levels are suitable to provide a stable low aluminum formulation having less than or equal to about 1 part per million (ppm) of aluminum that is essentially free of buffer or chelating agent.
Another object of the invention relates to preparing a unit dose system in a sealed vessel comprising an aqueous solution of a therapeutic amount of 1.alpha., 25-dihydroxycalciferol having oxygen levels less than or equal to 2.0% oxygen in the headspace.
Yet another object of the invention relates to a process for preparing compositions of 1.alpha., 25-dihydroxycholecalciferol having an amount of less than or equal to 2.0% oxygen in the headspace of a container. Preferably, the container is a unit dose vial.